Tetrazoles have found applications in various domains including material science, energetic materials, coordination chemistry, organic synthesis, and especially medicinal chemistry, due to the fact that 5-substituted tetrazoles (5-ST) are bioisosteres of carboxylic acids. Therefore, there is a need of novel methods for introducing a tetrazole functional group in compounds, e.g. in organic molecules.
The 1,3-dipolar cycloaddition (Huisgen reaction) of azides and alkynes leads to 5-membered triazole heterocycles and has gained considerable interest in the field of organic synthesis since the development of copper (I)-catalysed procedures by Medal and Tornøe. Copper-catalysed azide-alkyne cycloaddition (CuAAC) is a well-known “click” reaction, which is very general and has many attractive features, including: high or quantitative yields, robustness, insensibility, orthogonality, and compatibly with biological and polymerization conditions (Meldal, M. and Tomoe, C. W., Chemical Reviews 2008, Vol. 108, pp. 2952-3015.). A particularly advantageous aspect of CuAAC is that it allows orthogonal ligation reactions, which means that a dedicated set of reaction conditions will lead to a ligation reaction occurring specifically on a functional group of a molecule, without affecting the others.
Due to the popularity of CuAAC reaction, many libraries of compatible azides and alkynes are available. However, there is a need from improvement of the selectivity of CuAAC reactions and/or reduction of the number of steps for the synthesis of complex molecules. Therefore, there is still a need for novel reactants having specific features advantageous for CuAAC and presenting a variety of reactive groups, especially tetrazoles groups. There is also a need for reactants comprising “latent” or “hidden” functional groups, i.e. groups which will not react in CuAAC conditions, but may be easily converted to azide or alkyne when another reactive group is required, thus allowing sequential CuAAC reactions.
The applicant surprisingly established that alpha-hydroxy-beta-azido-tetrazoles could be useful molecular scaffolds for chemical synthesis, in particular for sequenced synthesis. Therefore, the applicant conceived and successfully reduced to practice the manufacture of alpha-hydroxy-beta-azido-tetrazoles and their use as reactant, especially in “click” reactions.